The overarching theme of the Program Project Grant (PPG) is that spontaneous DNA damage drives major components of aging by causing DNA mutations and eliciting adverse cellular responses, e.g., apoptosis, cellular senescence. The central hypothesis of Project 2 is that low levels of the highly toxic DNA double-strand breaks (DSBs) are a cause of aging, both through cellular end points and through DNA mutations. In the new Project 2 we will test this hypothesis by studying the role of DSBs in promoting the molecular and cellular phenotypes associated with aging. In two specific aims we will (1) further analyze the pro-aging effects of DSBs in WT and Ercc1-/?7 and Ku80-/- mice and (2) comprehensively determine the landscape of somatic mutations in liver of WT and Ercc1-/?7 and Ku80-/- mice, with a focus on genome structural variations that typically result from erroneous repair of DSBs. We will also test if the pro-longevity interventions developed by our collaborators do not only affect survival of cells and tissues, but also prevent or dampen genome instability.